rs4574

Variant names:

• chr9-124414882-A-G
• rs4574
• NM_002799.4:c.116T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002799.4(PSMB7):​c.116T>C​(p.Val39Ala) variant causes a missense change. The variant allele was found at a frequency of 0.431 in 1,612,794 control chromosomes in the GnomAD database, including 153,477 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16512 hom., cov: 31)
  • Exomes 𝑓: 0.43 (136965 hom.)
• Consequence: PSMB7 NM_002799.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.36
• Publications: 53 publications found

Genes affected

PSMB7 (HGNC:9544): (proteasome 20S subunit beta 7) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Expression of this catalytic subunit is downregulated by gamma interferon, and proteolytic processing is required to generate a mature subunit. A pseudogene of this gene is located on the long arm of chromosome 14. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.8055054E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002799.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB7	NM_002799.4	MANE Select	c.116T>C	p.Val39Ala	missense	Exon 2 of 8	NP_002790.1	Q99436-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB7	ENST00000259457.8	TSL:1 MANE Select	c.116T>C	p.Val39Ala	missense	Exon 2 of 8	ENSP00000259457.3	Q99436-1
	PSMB7	ENST00000916860.1		c.116T>C	p.Val39Ala	missense	Exon 2 of 9	ENSP00000586919.1
	PSMB7	ENST00000894504.1		c.116T>C	p.Val39Ala	missense	Exon 2 of 9	ENSP00000564563.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69191 AN: 151760 Hom.: 16500 Cov.: 31

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.401 AC: 100471 AN: 250412 AF XY: 0.402

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.239

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.429 AC: 626386 AN: 1460916 Hom.: 136965 Cov.: 41 AF XY: 0.427 AC XY: 310667 AN XY: 726730

African (AFR) AF: 0.602 AC: 20150 AN: 33460

American (AMR) AF: 0.325 AC: 14497 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 9134 AN: 26124

East Asian (EAS) AF: 0.226 AC: 8980 AN: 39680

South Asian (SAS) AF: 0.438 AC: 37759 AN: 86184

European-Finnish (FIN) AF: 0.407 AC: 21701 AN: 53376

Middle Eastern (MID) AF: 0.387 AC: 2229 AN: 5760

European-Non Finnish (NFE) AF: 0.438 AC: 486540 AN: 1111376

Other (OTH) AF: 0.421 AC: 25396 AN: 60350

GnomAD4 genome AF: 0.456 AC: 69248 AN: 151878 Hom.: 16512 Cov.: 31 AF XY: 0.449 AC XY: 33361 AN XY: 74236

African (AFR) AF: 0.595 AC: 24624 AN: 41404

American (AMR) AF: 0.346 AC: 5274 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3466

East Asian (EAS) AF: 0.242 AC: 1246 AN: 5154

South Asian (SAS) AF: 0.412 AC: 1982 AN: 4816

European-Finnish (FIN) AF: 0.404 AC: 4254 AN: 10524

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29169 AN: 67942

Other (OTH) AF: 0.416 AC: 875 AN: 2104

Alfa AF: 0.433 Hom.: 65469

Bravo AF: 0.462

TwinsUK AF: 0.443 AC: 1642

ALSPAC AF: 0.431 AC: 1661

ESP6500AA AF: 0.607 AC: 2673

ESP6500EA AF: 0.435 AC: 3739

ExAC AF: 0.408 AC: 49510

Asia WGS AF: 0.323 AC: 1127 AN: 3478

EpiCase AF: 0.420

EpiControl AF: 0.413

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.000098	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.7	N
PhyloP100		6.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.42
ClinPred		0.015	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.71
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4574; hg19: chr9-127177161; COSMIC: COSV52330411;